The association between the menopause and bone loss has long been recognized yet the underlying mechanism responsible for this phenomenon remains unclear. This project seeks to answer some of the basic questions on the role of estrogen deficiency in the induction of bone loss with a particular focus on the involvement of the calcium -vitamin D-PTH endocrine system. A rat model of ovarian dysfunction-induced osteopenia will be used to study the interaction of ovarian function, skeletal remodeling and the calcium-vitamin D endocrine system. The preliminary results from humans, as shown in Project 5, and our animal studies on the treatment of osteoporosis using combined intermittent PTH and estrogen administration are promising. We will further examine the efficacy of treatment at the different stages of bone loss and explore the intracellular signalling mechanism of the anabolic action of PTH. We will study the cellular mechanism of bone loss in the period immediately subsequent to estrogen withdrawal and during the natural reversal phase from estrogen deficiency resulting from gonadotropin releasing hormone agonist action. We will also study the interaction of ovarian function, dietary calcium intake and vitamin D on bone remodeling in our animal model seeking answers that are difficult to obtain in humans. Exploratory experiments in the role of C- terminal PTHrP as a bone resorption regulatory factor are also proposed. This project provides a conceptual link between Project 1, which will investigate factors that regulate the osteoclast at the cellular level an the use of rabbit model of estrogen deficiency-induced osteoporosis in Project 3, to human studies of the effects of estrogen on skeletal remodeling in postmenopausal women with primary hyperparathyroidism and the treatment of postmenopausal women with PTH and estrogen, in Projects 4 and 5. In this capacity our animal models will continue to test the physiological relevance of findings in isolated bone cells in vitro and will produce useful information on the efficacy and underlying mechanisms of new preventive and therapeutic strategies for postmenopausal osteoporosis.